[Rhonda]: We're talking about aging and also brain inflammation and, I mean, obviously,
there's been some interesting studies on sulforaphane in the brain.
[Jed]: Yeah.
So this is an area where we're actually spending a lot of our time now, is partnering on clinical
trials that are looking at just that.
So it turns out that the neurologists and those who have been studying the brain and
diseases of the brain for a long time in, I guess, the fairly recent past have determined
that inflammation is a huge component of a number of those conditions.
Schizophrenia, autism, Alzheimer's are among them.
And so we can we can speculate as to how that inflammation has an effect.
As far as I'm aware, you don't see increases in brain volume.
It's not that kind of inflammation, but markers of inflammation clearly are up in people with
these conditions and can be reversed in some cases with anti-inflammatory drugs.
And so people have come to us recently with the question, "Okay, we know sulforaphane
reduces inflammation.
You know, can it possibly help with autism, Alzheimer's and schizophrenia?"
The three that we're actually looking at.
I should back up, though, and say that sulforaphane, and isothiocyanates like it, have many effects.
They do affect many pathways.
We talked about Nrf2.
I may have made it seem like that was the best thing since sliced bread, and the only
thing.
It's not the only thing.
We also mentioned antibiosis, selective antibiosis against Helicobacter.
What we haven't talked about yet is the fact that sulforaphane actually inhibits the NF-kappaB
pathway, which is one of the main inflammatory pathways in the body.
And there's even some, as it's called, crosstalk between the Nrf2 pathway and the NF-kappaB
pathway, so the inflammatory and cytoprotective pathway.
Sulforaphane also, sorry, up-regulates the so-called heat shock response.
And I'll try to tie these together in a second.
But there are a number of other pathways in which it's active, the mTOR pathway is another.
So with all of these biochemical pathways that sulforaphane targets, many of them seemed
to come together in a few of the neurodegenerative or neurodevelopmental diseases.
And so autism was really the first one that I guess I can say was put in our lab or came
to our attention.
So Dr. Andy Zimmerman, a colleague at...who was at the time at Harvard Medical School
and the Mass General Hospital came to Paul Talalay back, I don't know exactly when, 2008
or 2009 or 2010 or somewhere in that range.
And Andy Zimmerman had shown previously, this was published in 2007, that the so-called
fever response of children with autism was real.
He sort of codified it and got it in print.
Apparently, psychiatrists and caregivers had been commenting anecdotally for a long time
that some of their charges, their kids or the people they're giving care to who had
autism, when they got a fever, they got better.
Their symptoms reversed or relapsed.
So autism is characterized by a number of things including repetitive motions, not making
eye contact, social and behavioral impairment, if you will.
And so a lot of these characteristics got a lot better when kids had fevers.
And so back to Dr. Zimmerman, he knew that we and others had shown that sulforaphane
was effective in up-regulating the heat shock response.
And so his question to Paul was, "Hey, why don't we see if sulforaphane also helps autism
because in half of the kids, when they get a fever, the symptoms go away or they don't
go away, but they rela-,..." [Rhonda]: Improve.
[Jed]: "They improve and that's likely related to this heat shock response.
Wouldn't it be interesting if sulforaphane has an effect?"
As all of us got thinking about it, there were clearly a number of other mechanisms
by which sulforaphane could be acting including reduction of inflammation and enhancement
of the antioxidant enzymes.
You know, more effective clearance of oxidative, reactive oxygen and reactive nitrogen species.
[Rhonda]: Right.
I never thought about heat shock protein playing a role in autism.
That's very interesting.
I mean, neurodegenerative diseases for sure, but I didn't...
And so that's an interesting connection he was making that I wouldn't have made, but
I can see how he is making it.
It's very interesting.
[Jed]: Yes.
So the paper is 2007, Curran, C-U-R-R-A-N, is the first author.
We'll get you a copy.
So yeah, it's a fascinating potential connection.
And so that was sort of...that was what got the collaboration started.
So we supplied broccoli sprout extract, and they, up in Boston, looked at, I guess it
was about 44 subjects, all men, all young men, boys, men.
As you probably know, autism is about four to one, male to female in terms of its incidence
in this country, anyway.
And less than or more than 1 in 100 kids now are born with autism.
So it's a huge problem.
I don't need to go into detail about why it's such a big problem, but, because you're an
expert on autism among other things.
[Rhonda]: Not really.
[Jed]: But, well, you've studied it.
So at any rate, we did this trial.
It was published in 2014.
We, for various reasons, biomarkers of inflammation of the Nrf2 pathway and heat shock response
were not evaluated in blood from those subjects.
But what we showed was a rather dramatic reduction in many of the symptoms of autism in about
half of the subjects compared to placebos.
Those who were given placebo instead of broccoli sprout extract in which there was no detectable
change.
[Rhonda]: I think it was, like, a 37% improvement in, if I remember correctly from your paper.
Yeah, it was very, very robust from a small amount.
[Jed]: It was dramatic.
Right, the n was small, the number of subjects was small, but it was a dramatic improvement.
I am so sad that we never got the biomarker data from those subjects, although theoretically,
it's still available.
As a result of that trial, a lot of people got interested in the possibilities.
And so Dr. Zimmerman and his team, including the Cullman Chemoprotection Center here, have
a follow-up grant from the Department of Defense to study a younger cohort, male and female,
boys and girls, about 50 subjects.
But a similar trial design and it is going to be...it is biomarker-rich.
So we've already done a pilot study with 10 subjects in which we evaluated...
We refined our ability to collect samples and to process the biomarker samples.
We're collecting blood from all of them.
And this is a trial design where, half of them, half of the subjects are getting, actually,
Avmacol, one of the supplements, the dietary supplements, the one with glucoraphanin and
myrosinase, half of them are getting that, half of them are getting a placebo for, I
think, it's 15 weeks, for about the same amount of time as we gave subjects in the previous
trial.
Biomarker-rich, then there's a washout period, and then everybody goes on the sulforaphane
product, the Avmacol, for another 15 weeks.
Dr. Hua Liu and I...she's doing most of the biomarker work here at Hopkins.
She and I were just up in Worcester, Massachusetts.
The team is now at UMass Medical Center in Worcester, Massachusetts.
They've processed about a third of the subjects.
So we're about a third of the way through completing the trial.
And we're very excited, obviously, about what we may find and about getting to the task
of processing these biomarkers.
[Rhonda]: Very exciting.
And what was the dose difference from the first trial?
The first trial, the dose of... [Jed]: Well, it's a little complicated, but
if you bear with me, the first trial delivered sulforaphane-rich broccoli sprout extract.
[Rhonda]: Okay.
[Jed]: Okay.
Remember that's 70% bioavailable, okay.
This trial's delivering glucoraphanin plus myrosinase.
It's calibrated to deliver about the same amount as the previous trial.
So between 100 and 150 micromoles per subject per day.
[Rhonda]: Is there a reason why you're not doing a dose response or trying higher doses,
as well, to see if there's a more robust effect?
[Jed]: The next trial will do that.
[Rhonda]: Okay, so that's in the pipeline?
[Jed]: Well, it's in this pipeline.
[Rhonda]: Okay.
[Jed]: Yeah.
So, I mean, look, after a trial like this, especially one where we were not able to publish
biomarker results, there are many people saying, "Wow, that's really interesting, but it's
got to be repeated."
So we and others are trying to repeat it just essentially as closely as possible to the
way it was designed.
You know, it does make sense and it's unfortunate.
If these trials weren't so damned expensive, I mean, we could try all...
[Rhonda]: It's expensive and long to do.
[Jed]: We could try all conditions.
[Rhonda]: I know, I imagine.
It's very, very exciting.
[Jed]: It's exciting, but it's very expensive, its labor-intensive, and it also...you know,
you've got the hopes, and fears, and desires, and tears of a lot of people involved.
These are conditions that that hurt to see people going through.
And so to do a whole bunch of trials with a whole bunch of conditions might also make
the people who are suffering from these conditions really think that this is...that we already
have the answer.
This is why I'm so afraid of some of the cancer prevention trials that are being done.
You know, people get on their high horse and they don't know what they're talking about.
You know, again, one of the most frequently heard things, for me, is, "Oh, scientists
at Johns Hopkins say this cures cancer."
I mean, I've heard that said about so many things, not just, certainly not just our work.
It ain't true.
We would love for it to be true, but same thing with autism, I guess if it were cheap
and easy to do and nobody cared about the subjects involved, there'd be a lot of trials,
a lot of them would be lousy trials, and a lot of people would have their hopes raised
only to maybe 10 or 15 years down the road find out that, yeah, those trials weren't
really done that well.
So all of the oversight, all of the self-criticism and the peer criticism is probably worth it
because I think it does serve a purpose.
Anyway, back to the story, so, enough philosophizing.
So we have this follow-up trial underway.
Interestingly, there are four other, additional autism trials using all using Avmacol, and
this is if it doesn't work, I'm to blame because I identified it as something that looked like
it was the best of what was out there, and I got the company to agree...
[Rhonda]: I mean, this is something that's available for people right now.
[Jed]: It's available, and we know that it produces sulforaphane and we know that it's
a decent product and it has been through all sorts of quality assurance.
But so when people who came to us and said, "We'd like to do an autism trial.
We'd like to model it after Andy's original trial, essentially, try to replicate the findings.
We want more of that sulforaphane that you produced for it."
And my answer has had to be, "I don't have any more.
And I'll show you, as my witness, I'll show you our freezer and show you that we don't
have any more in our clinical freezer.
So we just can't produce any more."
And so we had to suggest that people switch to something commercial.
So four other studies, one of them has finished its patient accruals at UCSF, and we're in
the process now of evaluating biomarkers, and they're using metabolomics to evaluate
biomarkers.
They're looking at small molecules produced by the various metabolic pathways that are
either induced, or up-regulated or not and hope to be able to make some correlations
with symptom reduction and biochemistry.
There is a trial just starting at the University of North Carolina, there's a trial at Rutgers.
I'm not sure how far along they are, pretty far along, I think.
And all three of those trials are about the same order of magnitude as our original trial,
20 to 50 patients or subjects.
The other trial is in China and there are, I'm going to get this wrong, there are either
120 or 180 subjects.
And that's just starting to study drug or supplement is they're...and this is at a school
for autistic kids in Changsha, China.
And you can read the descriptions of most of these trials, I think all of them, on clinicaltrials.gov,
which is the government's database for clinical trials.
So, again, all these studies are looking at biomarkers of inflammation, as you say, IL-6
is one of the key markers that people are looking at, COX-2, TNF-alpha.
The supposition is that those markers are going to go down.
The supposition is that markers of Nrf2 activation are going to go up, and heat shock protein
markers are going to go up.
We'll see.
[Rhonda]: Well, I mean, it's been shown in people that don't have autism that are given
sulforaphane at least, I guess, it may depend on the dose, but it has been shown.
The heat shock protein, that really caught my attention.
I came across it when I was reading about sulforaphane and how it can be neuroprotective
for Alzheimer's disease, Parkinson's, and even Huntington's.
These are all diseases of protein aggregation of which heat shock proteins play a major
role in repairing and preventing, both.
They do both.
So I was very surprised.
I guess not that, it wasn't that shocking once I found out that sulforaphane activates,
because it is a stress response pathway, heat shock proteins do respond to stress like heat
stress.
So I guess I wasn't that shocked, but I was a little surprised at first to see that it
plays a role.
And possibly, that's how it's helping prevent and protect against some of these neurodegenerative
diseases.
[Jed]: Very possible, yeah,